Despite recent improvements in hospital discharge rates from in-hospital pediatric cardiac arrest, discharge rates and neurologic outcome from out-of-hospital pediatric cardiac arrest remains poor. For adult cardiac arrest victims and newborns with hypoxic-ischemic encephalopathy, hypothermia is the only available treatment, although it does not provide complete neuroprotection in all adults or newborns. For out-of-hospital pediatric cardiac arrest, a recent trial failed to demonstrate improved functional outcome, in part because of the 5.9-hour delay in inducing hypothermia. To minimize this delay, we developed a simple yet innovative technique of transnasal cooling. Dry air at ambient temperature is passed through standard nasal cannula and out of the mouth to produce evaporative cooling of the nasal passages and a countercurrent heat exchange with cephalic arterial blood. An ongoing safety trial in adults indicates the feasibility of reducing core temperature without adverse effects on the nasal passages. Pilot data in large animals relevant to human toddlers and juveniles indicate rapid, uniform and preferential brain cooling compared to the body core. Preliminary work in a newborn animal model of asphyxic cardiac arrest indicates nearly complete histological neuronal protection with early initiation of transnasal cooling. However, the rate of brain cooling was slower in newborn and infant animals than in toddler and juvenile animals, possibly because of a smaller nasal turbinate surface area and underdeveloped nasal capillary density and blood flow. To better define maturational effects, we will study transnasal cooling efficacy after asphyxic cardiac arrest and resuscitation in animals at two ages relevant to infants and toddlers. These age groups have the highest incidence of asphyxic arrest. In Aim 1, we will measure the time course of cooling in different brain regions and body core after resuscitation to assess the effective range of airflow rates that can cool the brain without potential adverse effects on the pulmonary circulation. We will determine whether the brain is cooled uniformly, in contrast to the delayed subcortical cooling attained with cooling helmets. We will also determine whether the brain is cooled more rapidly than the body core. Prevention of overcooling the heart should minimize the risk of arrhythmias. In Aim 2, we will initiate transnasal cooling immediately or two hours after resuscitation and quantify neuronal histopathology in highly vulnerable brain regions to assure efficacy of neuroprotection over a range of clinically relevant delays. We will determine whether the rapid brain cooling afforded by the transnasal technique provides superior protection compared to 24 hours of whole body surface cooling. Because of its simplicity, portability, and low cost, transnasal cooling potentially could be used by emergency medical personnel and paramedics in the field and in both small and large hospital emergency rooms for early initiation of brain cooling prior to maintenance with standard surface cooling. It could eventually be deployed in low resource regions of the world, thereby having a transformative impact in expanding the efficacy and utilization of therapeutic hypothermia.